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UK – GlaxoSmithKline v Wyeth Holdings

20 May 2016

GlaxoSmithKline UK Limited v Wyeth Holdings LLC, High Court of Justice of England & Wales (Patents Court), London, UK, Carr J, 12 May 2016, Neutral Citation Number: [2016] EWHC 1045 (CH)

Carr J has upheld the validity of Wyeth’s patent EP(UK) 2,343,308 relating to a combination product comprising a 2086 protein and a PorA protein used in meningitis B vaccines, and found that a number of the claims are infringed by GSK’s meningitis B vaccine, Bexsero.

GSK commenced proceedings seeking revocation of the patent, alleging lack of entitlement to two of the claimed priority dates, lack of novelty, obviousness (both conventional and AgrEvo), insufficiency and added matter. Wyeth counterclaim for infringement of a number of claims.

Claim construction
In construing the claim Carr J held that:

  1. References in the claims to “at least one PorA protein” were not limited to any particular type of PorA protein.
  2. Functional limitations in certain sub-claims (e.g. “for use as a vaccine”) require that there be a discernible effect in the treatment of meningitis B.
  3. The two elements of the claimed combination (PorA and 2086 proteins) did not have to act synergistically, despite reference in the patent to them being “complimentary”.
  4. Whilst the 2086 protein did not have to be effective against every meningitis B strain, the claims did not cover non-functioning 2086 proteins where the required efficacy came from PorA alone. The purpose of including one or more PorA proteins in the combination was to extend coverage to meningitis B strains against which the 2086 protein alone would be ineffective.

AgrEvo obviousness/insufficiency – plausibility
A large number of “plausibility” objections were pleaded in support of insufficiency/AgrEvo obviousness, various of which were not pursued by the close of the trial. Carr J set out the relevant legal principles (all undisputed) and noted that to be plausible, a claim must meet a certain threshold – there must be some credible (rather than speculative) disclosure resulting in a real reason for supposing that the invention will work across the scope of the claim.

Carr J’s views on construction, for example that the combination need not act synergistically, largely dispensed with the plausibility arguments. GSK argued that the data in the patent suggested that some strains of meningitis causing bacteria would not be killed by all 2086 proteins with 100% homology, and it was even less credible that proteins having 95% homology (as per claim 1) would have been effective. However, Carr J held that these data would not have led the skilled person to believe that proteins with a lesser degree of homology would not work, as to reach such a conclusion would require too much reliance on single assay results, which could reasonably be considered exceptions to the general trend. (He acknowledged that the experiments had been carried out on complicated biological systems, and therefore the skilled person would not expect a direct relationship between homology and assay data in every case).

Similarly, while the data in the patent showed that a lipidated 2086 protein was preferable to a non-lipidated protein, those data did not render it implausible that the non-lipidated protein would have a bactericidal effect, despite the assays in the patent supporting the fact that the effect was significantly reduced.

Finally, all assays in the patent used a potent adjuvant which was not claimed. Carr J considered that this did not render the claims implausible, as the skilled person would use their common general knowledge at the priority date, together with routine trial and error, to identify a suitable adjuvant, were one desirable to boost/reduce the immune response.

In relation to AgrEvo obviousness, it was accepted that the claims must not be arbitrary (i.e. must provide a technical contribution). Again, Carr J’s construction that the claims do not cover non-functioning 2086 proteins supported his finding that they were not AgrEvo obvious.

Added Matter
Interestingly, GSK’s added matter objection sought support from the EPO case law relating to selections from multiple lists. GSK suggested that if novelty in an invention arises from a selection from two lists, such a selection would constitute added matter if the selection was not found in the application as filed. Carr J held that, while such selections could amount to impermissible added matter, this was not a rigid rule, and one has to consider the general disclosure of the whole application as filed.

In this case, the specific sequence claimed was the subject of a number of the examples in the application as filed, therefore its importance would have been clear to the skilled reader. The application identified that the degree of sequence homology is preferably greater than 60%, and specifically identified a number of percentage homologies including those subsequently claimed in the patent. Carr J held that the skilled person would have understood that a homology of less than the claimed 95% would have had utility, but that the patentee had simply chosen a reasonable claim boundary. Finally, in selecting PorA to combine with the 2086 protein, Carr J noted that the patent expressly disclosed such a combination, and that the importance of PorA in vaccines of this type formed part of the common general knowledge.

While a number of the examples in the patent are absent from the first priority document, Carr J found that there was sufficient disclosure of a combination of PorA and 2086 protein in the other examples and the body of the patent which meant that, along with the common general knowledge of the importance of PorA, such disclosure would render the invention plausible.

In addition, GSK argued that while the priority document discloses multiple sequence clusters, it does not group the relevant sequences together to form the critical group that is central to the disclosure of the patent’s claims. Carr J found that each of the relevant sequences are disclosed and specified in the alternative in claim 1 of the patent. There was no requirement that they be disclosed in the absence of any other sequences in order for there to be a valid entitlement to priority. In addition, Carr J held that while the first priority document discloses (and prefers) mucosal delivery, it does limit the method of delivery to mucosal and therefore claims not so limited are still entitled to priority.

Given the finding of priority, a number of the prior art citations fell away.

The first citation relied on by GSK was an international patent application WO 01/52885 (“WO 885”). GSK alleged that this disclosed an effective Meningitis B vaccine composition comprising two components. The first component was identified in WO 885 by reference to a number of international patent applications, including WO99/57280 (“WO 280”). WO 885 included a list of antigens taken from WO 280, one of which was the claimed 2086 protein (although not among those proteins identified as preferred in WO 280). Carr J did not consider this disclosure in WO 885 to be a sufficiently individualised disclosure of the claimed sequence as the skilled person would be required to pluck out the relevant protein sequence from the list of 1510 proteins in WO 280, and the references to WO 280 in WO 885 are no more than a reference to the document as a whole and provide no technical information.

Carr J held that it would have been obvious to select the correct second component, although WO 885 was cited for anticipation only. Therefore there was no clear and unambiguous disclosure of the combined components, nor anticipation by inevitable result.

Secondly, GSK relied on a Cuban Vaccine, which was used prior to the first priority date, but whose composition was not published until 2009 (some years later). On the evidence before him, which included challenged evidence from witnesses who were not presented for cross examination, Carr J held that he was unable to conclude on the balance of probabilities that the composition of the vaccine used pre-priority was the same as that published in 2009. He noted that the vaccine was more likely than not to have varied over the years. In any event, Carr J held, applying the House of Lords case of Merrell Dow v Norton, that any prior use of the Cuban Vaccine would not have been an enabling disclosure. He reasoned that GSK had not proved that the skilled person could (without undue burden) have analysed the vaccine before the priority date and identified the presence of the relevant component in order to reproduce it. Finally Carr J noted that even had the relevant component been present in the Cuban Vaccine, it was in such low abundance that it would not have had any material contribution to the immune response of the vaccine and therefore did not disclose the same.

GSK also relied on Anderson. Anderson disclosed the antibody response of outer membrane vesicles (OMVs) in mice after mucosal administration of the vaccine. The composition of one of the OMVs used is now known to comprise components which may fall within the claim. However, in order to identify what was in the OMV at the priority date, one would have to have conducted lengthy research which was unlikely to have been attempted. If it had been, there was no guarantee that the skilled person would produce OMVs falling within the claim. As such, there was no enabling disclosure.

This aspect of Carr J’s decision highlights the importance of taking the correct approach to instructing experts. The expert evidence of Prof Heckels was considered to be tainted by hindsight, as he was provided with documents identifying the protein of interest prior to considering the prior art. Carr J considered that the selection of the claimed 2086 protein as a protein of interest from the prior art document (992) was not obvious when viewed without hindsight. Alternatively, he held that the skilled team would not have tried the relevant protein with a fair expectation of success.

Only the infringement of claim 3 was argued at trial (although claims 1, 2 and 18-20 were found to be infringed). This turned on matters of construction: claims 1 and 2 require a degree of sequence identity to the 2086 protein within the claimed combination (claim 1 requiring 95% identity and claim 2 requiring 97%). The absence of such a percentage identity in claim 3 was held to mean that 100% sequence identity was required. This is because: (i) the gradual narrowing of the claims down the claim cascade is sequential i.e. claim 1 (95% identity) is the widest, claim 2 (97% identity) is next and claim 3 is the broadest (100% identity); (ii) it was known that a single amino acid change could have functional effect and therefore if a lesser degree of specificity was intended it would have been identified; (iii) where something other than 100% identity is intended, the percentage had been specified and (iv) such a construction provided certainty as to the scope of claim 3.

The sequence identity of GSK’s product did not reach 100%, so of the claims asserted, only claim 3 was not infringed.

Read the judgment here.

Headnote by Claire Phipps-Jones, Bristows LLP